It has been known that, in living things such as mammals, histamine which is a biologically active endogenous factor functions as a neurotransmitter and has a pharmacological activity within a broad range (refer, for example, to Life Science, vol. 17, page 503 (1975)).
It has been made clear as a result of immunohistochemical studies that a histaminergic (producing) cell body is present on nodular papillary nucleus of posterior hypothalamus and also that a histaminergic nerve fiber is projected to a very broad range in brain and supports various pharmacological actions of histamine (refer, for example, to Journal of Comparative Neurology, volume 273, page 283).
The presence of histaminergic nerve in nodular papillary nucleus of posterior hypothalamus suggests that, in brain function, histamine plays an important role in the control of physiological functions particularly related to the functions of hypothalamus (such as sleeping, awaking rhythm, incretion, behavior of taking food and water and sex behavior) (refer, for example, to Progress in Neurobiology, volume 63, page 637 (2001)).
The fact that histaminergic nerve fiber is projected to the region related to maintenance of wakefulness (such as cerebral cortex) suggests the role played by histamine in adjusting the wakefulness or a cycle of awakening and sleeping. In addition, the fact that histaminergic nerve fiber is projected to many marginal structures such as hippocampus and amygdaloid complex suggests the role of histamine in the adjustment of autonomic nerve, in the control of emotion and motivated behavior and in the learning and memorizing process.
When histamine is released from producing cells, it plays its pharmacological actions as a result of action to specific polymer called a receptor on a cell membrane surface or in a target cell and conducts the adjustment of various physical functions. Until now, four kinds of histamine receptors have been found and, particularly as to a receptor participating in central and peripheral nerve functions of histamine, the presence of histamine H3 receptor has been shown by various pharmacological and physiological studies (refer, for example, to Trends in Pharmacological Science, volume 8, page 24 (1986)). Further, in recent years, human and rodential histamine H3 receptor gene has been identified and its presence has been clarified (refer, for example, to Molecular Pharmacology, volume 55, page 1101 (1999)).
Histamine H3 receptor is present in presynaptic membrane of central or peripheral nerve cells functioning as a self-receptor and controls not only release of histamine but also release of other neurotransmitters. Thus, histamine H3 receptor agonist, antagonist or inverse agonist regulates the liberation of histamine, noradrenaline, serotonin, acetylcholine, dopamine, etc. from nerve terminal. Release of the above-mentioned neurotransmitters is suppressed by a histamine H3 receptor agonist such as (R)-(α)-methylhistamine and is promoted by a histamine H3 receptor antagonist such as thioperamide or inverse agonist (refer, for example, to Trends in Pharmacological Science, volume 19, page 177 (1998)).